Calderone A, Thaik C M, Takahashi N, Chang D L, Colucci W S
Department of Medicine, Boston Medical Center, Boston, Massachusetts 02118, USA.
J Clin Invest. 1998 Feb 15;101(4):812-8. doi: 10.1172/JCI119883.
This study tested the hypothesis that nitric oxide (NO) and atrial natriuretic peptide (ANP) can attenuate the effects of adrenergic agonists on the growth of cardiac myocytes and fibroblasts. In ventricular cells cultured from neonatal rat heart, ANP and the NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP) caused concentration-dependent decreases in the norepinephrine (NE)-stimulated incorporation of [3H]leucine in myocytes and [3H]thymidine in fibroblasts. In myocytes, the NO synthase inhibitor NG-monomethyl-L-arginine potentiated NE-stimulated [3H]leucine incorporation. In both cell types, ANP and SNAP increased intracellular cGMP levels, and their growth-suppressing effects were mimicked by the cGMP analogue 8-bromo-cGMP. Furthermore, in myocytes, 8-bromo-cGMP attenuated the alpha1-adrenergic receptor-stimulated increases in c-fos. Likewise, ANP and 8-bromo-cGMP attenuated the alpha1-adrenergic receptor- stimulated increase in prepro-ANP mRNA and the alpha1-adrenergic receptor-stimulated decrease in sarcoplasmic reticulum calcium ATPase mRNA. The L-type Ca2+ channel blockers verapamil and nifedipine inhibited NE-stimulated incorporation of [3H]leucine in myocytes and [3H]thymidine in fibroblasts, and these effects were not additive with those of ANP, SNAP, or 8-bromo-cGMP. In myocytes, the Ca2+ channel agonist BAY K8644 caused an increase in [3H]leucine incorporation which was inhibited by ANP. These findings indicate that NO and ANP can attenuate the effects of NE on the growth of cardiac myocytes and fibroblasts, most likely by a cGMP-mediated inhibition of NE-stimulated Ca2+ influx.
本研究检验了一氧化氮（NO）和心钠素（ANP）可减弱肾上腺素能激动剂对心肌细胞和成纤维细胞生长的影响这一假说。在新生大鼠心脏培养的心室细胞中，ANP和NO供体S-亚硝基-N-乙酰-D，L-青霉胺（SNAP）导致去甲肾上腺素（NE）刺激的[3H]亮氨酸掺入心肌细胞以及[3H]胸腺嘧啶掺入成纤维细胞呈浓度依赖性降低。在心肌细胞中，NO合酶抑制剂NG-单甲基-L-精氨酸增强了NE刺激的[3H]亮氨酸掺入。在这两种细胞类型中，ANP和SNAP均提高了细胞内cGMP水平，且它们的生长抑制作用被cGMP类似物8-溴-cGMP模拟。此外，在心肌细胞中，8-溴-cGMP减弱了α1肾上腺素能受体刺激的c-fos增加。同样，ANP和8-溴-cGMP减弱了α1肾上腺素能受体刺激的前心钠素原mRNA增加以及α1肾上腺素能受体刺激的肌浆网钙ATP酶mRNA降低。L型钙通道阻滞剂维拉帕米和硝苯地平抑制了NE刺激的[3H]亮氨酸掺入心肌细胞以及[3H]胸腺嘧啶掺入成纤维细胞，且这些作用与ANP、SNAP或8-溴-cGMP的作用无相加性。在心肌细胞中，钙通道激动剂BAY K8644导致[3H]亮氨酸掺入增加，这一作用被ANP抑制。这些发现表明，NO和ANP可减弱NE对心肌细胞和成纤维细胞生长的影响，最可能是通过cGMP介导的对NE刺激的钙内流的抑制作用。
